From the nature of processes to death, cell death is categorized into two types, necrosis and apoptosis. Necrosis is accidental cell death that accidentally occurs due to physical/chemical factors, etc. In contrast, apoptosis is cell death deeply involved in morphogenesis during the developmental process, tissue formation, maintenance of homeostasis, biological defense, etc. to play a critical role in supporting the individual's life, and the process is regulated by a gene. Congenital or acquired disorders of these cell death processes excessively induce or prevent cell death to cause dysfunctions of various organs, leading to diseases (SAISHIN-IGAKU, 54, 825, 1999).
In recent years, it has been revealed that these types of cell death are deeply committed to the development or progress of various diseases (R. Sanders Williams, The New England Journal of Medicine, 341, 759, 1999). For example, diseases caused by increased cell death include neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, cerebellar degeneration, etc.), ischemic diseases (e.g., myocardial infarction, heart failure, apoplexy, cerebral infarction, ischemic acute renal failure, etc.), bone/joint diseases (e.g., osteoporosis, arthritis deformans, rheumatism, etc.), myelodysplastic diseases (e.g., aplastic anemia, etc.), hepatic diseases (e.g., alcoholic hepatitis, viral hepatitis, etc.), diabetes mellitus, AIDS, etc. [Nippon Rinsho, 54, 1996; Extra Issue: Igaku-no-Ayumi, page 8, 1997, etc.].
Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine produced from immunopathologically mediated cells, hypophysis, etc. in concert with an invasion into the body, and are known to be located upstream of the inflammatory cytokine cascade to control inflammatory responses (Annual Reports in Medicinal Chemistry, 33, 24, 1998; Advances in Immunology, 66, 197, 1997). Furthermore, it is becoming clear that MIF is involved in the proliferation and differentiation of fat cells, cancer cells, etc. and plays an important role not only in immune response but also in various biological reactions (International Journal of Molecular Medicine, 2, 17, 1998). As the cells/tissues which express MIF, the following are known: T cells, monocytes/macrophages, mesangial cells, tubular epithelial cells, corneal epithelial cells, hepatocytes, oocytes, Sertoli cell, keratinocytes, osteoblasts, synovial cells, fat cells, astrocytes, cancer cells, mucous membranes, hypophysis, etc. As examples for MIF to take part in human diseases, there are reports showing that MIF level markedly increased in synovial fluid or serum from the patient with rheumatism, in alveolar lavage fluid from the patient with acute respiratory distress syndrome, in urine collected during rejection from the patient who received a kidney transplant, and in serum from the patient with acute myocardial infarction, diabetes mellitus, systemic lupus erythematosus, Crohn's disease or atopic dermatitis, when compared to healthy individuals. As an example that suppression of MIF leads palliation of symptoms, there is an experiment using anti-MIF neutralizing antibody. That is, in animal disease model of nephritis, hepatitis, pneumonia, arthritis, endotoxin shock, etc., markedly improving effects are observed in the group administered with anti-MIF neutralizing antibody (International Journal of Molecular Medicine, 2, 17, 1998).
As to the relationship between this MIF and cell death, it is reported that apoptosis mediated by anti-IgM antibody in a mouse B cell line is inhibited by reduced production of MIF (Microbiology and Immunology, 43, 61, 1999). However, the relationship between MIF and cell death is unknown except for the mouse B cell line, and moreover, there is no report on mechanism of cell death in which MIF is involved.
Recently factors controlling induction of apoptosis have been revealed one after another with the development of studies on cell death, especially studies on apoptosis. As a result, many attempts to directly repress apoptosis have been made using low molecular weight compounds which were searched for targeting these controlling factors. Among others, caspase inhibitors targeting caspase, which work on the final stage of apoptosis, have been actively studied, but any of them has not been clinically applied [JIKKEN IGAKU (Experimental Medicine), 19, 1726, 2001]. Also with necrosis, studies have been made on chaperones such as HSP70, etc. but clinical application has not been made yet (Essays in Biochemistry, 32, 17, 1997). For these reasons, it has been earnestly desired to develop a safe and potent cell death inhibitor and a screening system for searching the cell death inhibitor.